1. Field of the Invention
The present invention relates, in general, to a method for treating or preventing certain medical clinical conditions with isoflavones. In particular, the present invention relates to a method of treating or preventing one or more of the following medical conditions: hepatic steatosis, steatohepatitis, insulin resistance, impaired glucose tolerance, syndrome X, abnormal platelet function, or abnormal vascular reactivity, with compositions containing isoflavones.
2. Related Art
Dietary soy protein has been shown to be hypocholesterolemic in human and animal studies (Carroll, K. K. and Kurowska, E. M., J. Nuir. 125:594S-597S (1995)). In humans, the cholesterol-lowering effect has been observed primarily in persons that are hypercholesterolemic prior to dietary intervention (Anderson, J. W., et al., N. Engl. J. Med. 333:276-282 (1995)). Soy protein diets have been particularly beneficial in the treatment of type II hyperlipoproteinemia (Sirtori, C. R., et al., Lancet 1:275-277 (1977); Sirtori, C. R., et al., J. Nutr. 125:598S-605S (1995)), which is characterized by elevated plasma LDL cholesterol (type IIa) or plasma LDL and VLDL cholesterol and triglyceride (type IIb). Hyperlipidemia is associated with the development of atherosclerosis, cardiovascular disease (CVD), and non-insulin dependent diabetes mellitus (NIDDM) (Despres, J.-P., et al., Arteriosclerosis 10:497-51 1 (1990)). Therefore, a hypocholesterolemic effect of soy protein can lower CVD and NIDDM risk.
Hypotheses have been proposed for mechanisms responsible for the cholesterol-lowering effect of soy protein (Anthony, M. S., et al., Am. J. Clin. Nutr. 68:1390S-1393S (1998); Potter, S. M., Nutr. Rev. 56:231-235 (1998); Sirtori, C. R., et al., Nutr. Metab. Cardiovasc. Dis. 8:334-340 (1998)). The soy protein amino acid composition, specific soy peptides and globulins, and the isoflavones and saponins associated with soy protein all have been suggested as factors participating in the hypocholesterolemic response. The liver centrally regulates whole-body cholesterol excretion through the production and secretion of bile. Therefore, a mechanism responsible for the hypocholesterolemic effect of soy protein likely includes normalization of aberrant hepatic cholesterol and bile acid metabolism. The liver also centrally regulates plasma cholesterol and triglyceride concentrations through production, secretion, and catabolism of apolipoprotein B (apoB). Furthermore, visceral obesity and elevated portal-hepatic free fatty acid flux induces hepatic steatosis and elevates the production of triglyceride-rich apoB-lipoproteins (Despres, J.-P., et al., Arteriosclerosis 10:497-511 (1990)). Therefore, a mechanism responsible for the hypocholesterolemic effect of soy protein can also include normalization of aberrant hepatic fatty acid and triglyceride metabolism.
Obese (fa/fa) Zucker rats are hyperinsulinemic, hyperlipoproteinemic, and develop hepatic steatosis within a few weeks after birth (Krief, S. and Bazin, R., Proc. Soc. Exp. Biol. Med. 198:528-538 (1991)). This rat can be used as a model system for symptoms associated with the development of CVD and NIDDM (St. John, L. C. and Bell, F. P., Atherosclerosis 86:139-144 (1991); Kasiske, B. L., et al., Hypertension (Suppl. 1) 19:1110-1115 (1992)). Markedly elevated pancreatic insulin secretion suppresses hepatic fatty acid catabolism and stimulates hepatic lipogenesis and fatty acid esterification. Elevated triglyceride and cholesteryl ester availability up-regulates secretion of apoB-lipoproteins and induces lipid storage in cytosolic droplets (Fukuda, N., et al., J Biol. Chem. 257:14066-14072 (1982)). Furthermore, there is an absence of the feeding-induced diurnal rise-and-fall of hepatic cholesterogenesis in adult male obese rats (Lin, R. C., Metabolism 34:19-24 (1985)), and fecal neutral sterols are 50% lower in obese rats than in lean rats (McNamara, D. J., Metabolism 34:130-135 (1985)). Expression of the hepatic LDL receptor is 60% lower in obese rats than in lean rats, without a difference in LDL receptor mRNA (Liao, W., et al., Endocrinology 138:3276-3282 (1997)). The diurnal rhythm of hepatic cholesterol 7xcex1-hydroxylase has also been shown to be absent in obese rats (Tang, P. M., et al., Biochem. Biophys. Res. Commun. 150:853-858 (1988)).
Blood platelets also play an integral role in the development of CVD (Ross, R., N. Engl. J Med. 314:488-500 (1986)). Arterial cholesterol deposition and blood platelet sensitivity are elevated by plasma LDL and lowered by plasma HDL (Miller, N. E., et al., Clin. Res. 282:1741-1744 (1981), Surya, I. I. and Akkerman, W. N., Heart J. 125:272-275 (1993)). The variation in platelet sensitivity found among species has been shown to correlate directly with susceptibility of the species to CVD (Hayes, K. C. and Pronczuk, A., Comp. Biochem. Physiol. 11313:349-353 (1996)). Furthermore, the plasma LDL cholesterol-to-HDL cholesterol ratio has been found to vary directly with platelet sensitivity both across and within species. Platelet activation is accompanied by release of compounds from intraplatelet granules that promote atherosclerotic lesion formation (Ross, R., et al., Circulation (Suppl III) 70:77-82 (1984)). For example, platelet-derived growth factor stimulates vascular smooth muscle cell migration and proliferation in the arterial intima. Activated platelets also release 5-hydroxytryptamine (5HT), commonly known as serotonin, which plays a role in the pathophysiology of essential hypertension (Nityanand, S., et al., Life Sci. 46:367-372 (1990)). Dietary soy protein rich in isoflavones has been shown to reduce atherosclerotic lesion development in male cynomolgus monkeys fed an atherogenic diet (Anthony, M. S., et al., Arterioscler. Thromb. Vasc. Biol. 17:2524-2531 (1997)). An inhibitory effect of isoflavone-rich soy protein on platelet aggregability has been reported in female rhesus monkeys (Williams, J. K. and Clarkson, T. B., Coronary Artery Dis. 9:759-764 (1998)). These effects of isoflavone-rich soy protein can result in part from a reduction in the plasma LDL cholesterol-to-HDL cholesterol ratio. Another study has shown rapid inhibition of vasoconstriction in stenotic arteries of female macaques after intravenous infusion of the soy isoflavone genistein (Honore, E. K., el al., Fertil. Steril. 67:148-154 (1997)). Improved systemic arterial compliance has also been shown after dietary isoflavone supplementation in menopausal women (Nestel, P. J., et al., Axterioscler. Thromb. Vase. Biol. 17:3392-3398 (1997)).
The present invention provides a method of preventing or treating the symptoms of one or more of the following clinical medical conditions: hepatic steatosis, steatohepatitis, insulin resistance, impaired glucose tolerance, syndrome X, abnormal platelet function, or abnormal vascular reactivity. This method comprises administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid.
The present invention further provides a method of preventing or treating the symptoms of one or more of the aforementioned clinical medical conditions by administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid in combination with soy protein.
The present invention also provides a method of preventing or treating the symptoms of one or more of the aforementioned clinical medical conditions by administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid in combination with dietary ingredients or supplements other than soy protein.
The present invention further provides a method of preventing or treating the symptoms of one or more of the aforementioned clinical medical conditions by administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid which is contained in an isoflavone-enriched fraction of soy protein.
The present invention also provides a method of preventing or treating the symptoms of one or more of the aforementioned clinical medical conditions by administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid which is contained in an isoflavone-enriched fraction of soy protein in combination with soy protein.
The present invention further provides a method of preventing or treating the symptoms of one or more of the aforementioned clinical medical conditions by administering to a subject having, or predisposed to, one or more of these conditions, a therapeutically effective amount of at least one isoflavonoid which is contained in an isoflavone-enriched fraction of soy protein in combination with dietary ingredients or supplements other than soy protein.
Further objects, advantages, and novel features of the present invention will become apparent from the following detailed description of the invention.